Process for the preparation of phosphonated N,N-disubstituted fatty amides

ABSTRACT

Phosphonated N,N-disubstituted fatty amides were prepared by the free radical addition of dialkyl phosphites to terminal and nonterminal double bonds of N,N-disubstituted amides. The free radical additions of the dialkyl phosphites to the unsaturated amides were initiated by irradiation with gamma radiation from cobalt-60. These new compounds exhibit antimicrobial activity.

A non-exclusive, irrevocable, royalty-free license in the inventionherein described throughout the world for all purposes of the UnitedStates Government, with the power to grant sublicenses for suchpurposes, is hereby granted to the Government of the United States ofAmerica.

This is a division of application Ser. No. 335,860, filed 2/26/73, nowU.S. Pat. No. 3,911,120.

This invention relates to new phosphorus-containing organic compoundsand to a novel process for the preparation of the new compounds. Moreparticularly, this invention relates to N,N-disubstituted long chainaliphatic amides, the acyl component of which is a normal, branched, orsubstituted alkenoic acyl group containing from 11 to 22 carbon atoms,the amide nitrogen of which may be derived from a dialkylamine,alkyl-alkoxyalkylamine, dialkoxyalkylamine, or nitrogenheterocyclic....typical amines being dibutylamines,N-methyl-N-alkoxy-ethylamine, di-ethoxyethylamine, and morpholines. Theacyl substituent referred to is generally pentavalent phosphorus.

The findings herein disclosed are considered remarkable in that in somenotable instances compounds that are closely related from the point ofview of chemical structure exhibit quite different effects against thesame microorganisms. For example, one compound may exhibit properties asa growth inhibitor against one particular microorganism while a closelyrelated compound may serve to promote increased growth for the samemicroorganism. Some of these new compounds exhibit a broad antimicrobialspectrum whereas others exhibit a selective antimicrobial spectrum. Someof the compounds produced by the process of this invention areN,N-dibutyl-9(10)-dibutylphosphonooctadecanamide,N,N-bis(2-ethoxyethyl)-9(10)-dibutylphosphonooctadecanamide,N-[9(10)-dibutylphosphonooctadecanoyl]-2,6-dimethylmorpholine,N-ethyl-N-(3-ethoxypropyl)-9(10)-dibutylphosphonooctadecanamide,N-[9,(10)-dibutylphosphonooctadecanoyl]piperidine,N-[9(10)-dibutylphosphonooctadecanoyl]-N'-methylpiperazine,N,N-dimethyl-9(10)-dibutylphosphonooctadecanamide,N[9(10)-dibutylphosphonooctadecanoyl]-4-methylpiperidine,N-methyl-N-butyl-9(10)-dibutylphosphonooctadecanamide,N-[9(10)-dibutylphosphonooctadecanoyl]morpholine,N-[11-dibutylphosphonoundecanoyl]-morpholine, andN-(12-acetyl-12-carboethoxydodecanoyl)-morpholine.

The new phosphorus-containing compounds of this invention were preparedby a novel procedure involving the free-radical addition of dialkylphosphites to terminal and nonterminal double bonds of N,N-disubstitutedamides. The free-radical additions were initiated by irradiation withgamma radiation from cobalt-60. The reaction to the internal double bondis unexpected since after attempts to initiate the reaction of dialkylphosphites with alkyl oleates by ultra-violet irradiation, bothreactants were recovered unchanged. (See "Phosphorus Derivatives ofFatty Acids. VII. Addition of Dialkyl Phosphonates to UnsaturatedCompounds," by R. Sasin, et al., which appears in the Journal ofAmerican Chemical Society, Vol. 81, pp. 6275-6277 (1959)).

The bioactivity of these various new phosphorus containing compounds hasbeen established in vitro but, as will be apparent to those skilled inthe arts pertaining to the growth inhibition of bacteria, yeast andmolds, the compounds, besides being used as such, will for utilitarianpurposes commonly be formulated using a diluent that can be eitherliquid, gel, or solid.

A wide variety of extending agents is operable, the only significantrequirement being that the diluent or extender be inert with respect tothe compound involved. Petroleum jellies, various alcohols and polyols,vegetable oils and the like are suitable.

ANTIMICROBIAL EVALUATION PROCEDURE

The micro-organisms used were obtained from stock cultures. DifcoDehydrated Mycological Agar at pH 7.0 was used to test the inhibition ofthe test organisms by the compounds being screened. Suspensions of thetest organisms were prepared by transferring a loop of spores intosterile saline. Hardened agar plates were inoculated by placing 3 dropsof the suspension onto the agar. The micro-organisms were spread overthe surface of the plates with sterile glass rods. These plates wereemployed in the activity estimation against microbial growth. Filterpaper discs, 6.5 mm. in diameter made from Whatman Number 1 filterpaper, were used to evaluate the compounds. The paper discs, wetteduntil they were completely saturated with the test compound, were placedon the surface of the agar plates inoculated with the testmicro-organisms. A minimum of three experiments, at different times,employing duplicate plates were made for each compound under test. Allplates were incubated at the optimum growing temperature for eachmicro-organism and the readings were taken after 24, 48, 72, and 120hour periods.

The micro-organisms used in the tests were Escherichia coli,Trichosporon capitatum, Trichodermavirde, and Candida lipolytica. Theywere obtained from stock cultures. The various data from antimicrobialactivity tests and elemental analyses are tabulated in Tables I and II,respectively.

A more detailed presentation of the material pertaining to the presentinvention can be found in the Journal of the American Oil ChemistsSociety, Vol. 49, No. 11, pp. 634-635 (1972), bearing the title "FreeRadical Addition of Dialkyl Phosphites to N,N-Disubstituted Amides ofUnsaturated Fatty Acids and Screening of the Products for AntimicrobialActivity."

The following examples are provided to illustrate specific embodimentsof the invention. Growth inhibiting properties are presented intabulated form. These examples are not intended to limit the inventionin any manner whatever.

EXAMPLE 1 N,N-Dibutyl-9(10)-dibutylphosphonooctadecanamide

Samples of 1.5 grams (0.0038 mole) of N,N-dibutyloleamide and 2.6 grams(0.0134 mole) of dibutyl phosphite were placed in a flask, mixed well,and exposed in the SRRL cobalt-60 (γ - radiation) source which had adose rate of about 0.95 Mr/hr to initiate free radical chain reaction.After irradiating for 18 hours (equivalent to about 17 megarads withthis source), the mixture was removed from the irradiation source,dissolved in Skelly B, passed through a column of activated alumina andstripped. The product, N,N-dibutyl-9(10)-dibutylphosphonooctadecanamide,had a phosphorus content of 5.01% (theory 5.27%).

EXAMPLE 2 N,N-Bis(2-ethoxyethyl)-9(10)-dibutylphosphonooctadecanamide

This compound was prepared by the procedure of Example 1 from 8 grams(0.0018 mole) of N,N-bis(2-ethoxyethyl)oleamide and 11 grams (0.0057mole) of dibutylphosphite. The product,N,N-bis(2-ethoxyethyl)-9(10)-dibutylphosphonooctadecanamide had aphosphorus content of 4.75% (theory 4.99%).

EXAMPLE 3 N-[9(10)-Dibutylphosphonooctadecanoyl]-2,6-dimethylmorpholine

This compound was prepared by the procedure of Example 1 from 8 grams(0.0020 mole) of N-oleoyl-2,6-dimethylmorpholine and 12.3 grams (0.0063mole) of dibutyl phosphite. The product,N-[9(10)-dibutylphosphonooctadecanoyl]-2,6-dimethylmorpholine had aphosphorus content of 5.34% (theory 5.40%).

EXAMPLE 4N-Ethyl-N-(3-ethoxypropyl)-9(10-)dibutylphosphonooctadecanamide

This compound was prepared by the procedure of Example 1 from 8 grams(0.0020 mole) of N-ethyl-N-(3-ethoxypropyl)-oleamide and 12.2 grams(0.0063 mole) of dibutyl phosphite. The product,N-ethyl-N-(3-ethoxypropyl)-9(10)-dibutylphosphonooctadecanamide had aphosphorus content of 5.18% (theory 5.25%).

EXAMPLE 5 N-[9(10)-Dibutylphosphonoctadecanoyl]piperidine

This compound was prepared by the procedure of Example 1 from 4 grams(0.0011 mole) of N-oleoylpiperidine and 6.7 grams (0.0034 mole) ofdibutyl phosphite. The product,N-[9(10)-dibutylphosphonooctadecanoyl]piperidine had a phosphoruscontent of 5.70% (theory 5.70%).

EXAMPLE 6 N-[9(10)-Dibutylphosphonooctadecanoyl]-N'-methylpiperazine

This compound was prepared by the procedure of Example 1 from 8 grams(0.0021 mole) of N-oleoyl-N'-methylpiperazine and 12.8 grams (0.0066mole) of dibutyl phosphite. The product,N-[9(10)-dibutylphosphonooctadecanoyl]-N'-methylpiperazine, had aphosphorus content of 5.32% (theory 5.55%).

EXAMPLE 7 N,N-Dimethyl-9(10)-dibutylphosphonooctadecanamide

The compound was prepared by the procedure of Example 1 from 8 grams(0.0026 mole) of N,N-dimethyloleamide and 15.1 grams (0.0078 mole) ofdibutyl phosphite. The product,N,N-dimethyl-9(10)-dibutylphosphonooctadecanamide, had a phosphoruscontent of 6.28% (theory 6.15%).

EXAMPLE 8 N-[9(10)-Dibutylphosphonooctadecanoyl]-4-methylpiperidine

This compound was prepared by the procedure of Example 1 from 8 grams(0.0022 mole) of N-oleoyl-4-methylpiperidine and 12.8 grams (0.0066mole) of dibutyl phosphite. The product,N-[9(10)-dibutylphosphonooctadecanoyl]-4-mthylpiperidine had aphosphorus content of 5.31% (theory 5.56%).

EXAMPLE 9 N-Methyl-N-Butyl-9(10)-dibutylphosphonooctadecanamide

This compound was prepared by the procedure of Example 1 from 8 grams(0.0023 mole) of N-methyl-N-butyloleamide and 13.4 grams (0.0069 mole)of dibutyl phosphite. The product,N-methyl-N-butyl-9(10)-dibutylphosphonooctadecanamide, had a phosphoruscontent of 5.35% (theory 5.68%).

EXAMPLE 10 N-[9(10)-Dibutylphosphonooctadecanoyl]morpholine

This compound was prepared by the procedure of Example 1 from 8 grams(0.0023 mole) of N-oleoyl-morpholine and 13.3 grams (0.0068 mole) ofdibutyl phosphite. The product N-[9(10)-dibutylphosphonooctadecanoyl]morpholine, had a phosphorus contentof 5.6% (theory 5.68%).

EXAMPLE 11 N-[11-Dibutylphosphonoundecanoyl]morpholine

This compound was prepared by the procedure of Example 1 from 8 grams(0.0032 mole) of 10-undecenoylmorpholine and 18.4 grams (0.0095 mole ofdibutylphosphite. The product, 11-dibutylphosphonoundecanoylmorpholinehad a phosphorus content of 6.71% (theory 6.90%).

EXAMPLE 12 N-(12-Acetyl-12-Carboethoxydodecanoyl)morpholine

Samples of 2 grams (0.0078 mole) of 10-undecenoylmorpholine and 30.9grams (0.237 mole) of ethyl acetoacetate were placed in a flask, mixedwell, and exposed in the SRRL cobalt-60 (γ -radiation) source toinitiate free radical chain reaction. After irradiating for 17 hours,the mixture was removed from the irradiation source and stripped underreduced pressure.

Analysis of the product, N-(12-acetyl-12-carboethoxydodecanoyl)morpholine: % G 65.78 (theory 65.76); % H, 9.87 (theory 9.73); % N, 3.68(theory 3.65).

SUMMARY OF THE INVENTION

This invention can best be described as (1) a process for thepreparation of phosphonated fatty amides utilizing gamma-radiation fromcobalt-60 to initiate a free-radical chain reaction to react morpholineswith dialkyl phosphite to yield products represented by the formula:##SPC1##

wherein R is an alkyl radical containing from one to four carbon atoms;(2) the products produced by the process of (1), which are phosphonateswith substantial antimicrobial activity, such as the productN(11-dibutylphosphonoundecanoyl)morpholine, which is derived from10-undecenoyl morpholine; (3) a process for the preparation of compoundsrepresented by either: ##STR1## wherein R is an alkyl radical containingfrom 1 to 4 carbon atoms, and R' contains an amide nitrogen which may bederived from a dialkylamine, alkyl-alkoxyalkylamine, or nitrogenheteroalicyclic, which process comprises reacting 1 mole of anN,N-disubstituted oleamide with about from 1 to 3 moles of a dialkylphosphite, using gamma radiation from cobalt-60 to initiate free-radicalreaction, and (4) the many phosphonated fatty amides produced by theprocess of (3).

                                      TABLE I                                     __________________________________________________________________________    Antimicrobial Activity of Phosphonated Fatty Amides                                                            Antimicrobial Activity.sup. a                                                 Micro-organism.sup. b                           Compound                      A   B   C   D                                __________________________________________________________________________    N,N-Dibutyl-9(10)-dibutylphosphonooctadecanamide                                                               xx   -  -   -                                N,N-Bis(2-ethoxyethyl)-9(10)-dibutylphosphonooctadecanamide                                                    xx   x  xx  x                                N-[9(10)-Dibutylphosphonooctadecanoyl]-2,6-dimethylmorpholine                                                   +   x  x   x                                N-Ethyl-N-(3-ethoxypropyl)-9(10)-dibutylphosphonooctadecanamide                                                 x   x  x   x                                N-[9(10)-Dibutylphosphonooctadecanoyl]piperidine                                                                +   x  x   xx                               N-[9(10)-Dibutylphosphonooctadecanoyl]-N'-methylpiperazine                                                     xx  xx  x   xx                               N,N-Dimethyl-9(10)-dibutylphosphonooctadecanamide                                                               x  xx  xx  x                                N-[9(10)-Dimethylphosphonooctadecanoyl]-4-methylpiperidine                                                     xx  xx  x   x                                N-Methyl-N-butyl-9(10)-dibutylphosphonooctadecanamide                                                          xx  xx  xx  x                                N-[9(10)-Dibutylphosphonooctadecanoyl]morpholine                                                                x   x  x   x                                N-[11-Dibutylphosphonoundecanoyl]morpholine                                                                    ++  ++  ++  ++                               N-(12-Acetyl-12-carboethoxydodecanoyl)morpholine                                                                x  ++  ++  +                                __________________________________________________________________________     .sup.a ++ = The zone of inhibition was at least 0.5 cm beyond disc at 120     hrs.                                                                          + = The zone of inhibition was less than 0.5 cm beyond disc at 120 hrs.       xx = Organism failed to grow on disc at 120 hrs.                              x = Slight growth on the saturated disc at 120 hrs.                           - = No inhibition detectable.                                                 .sup.b A = Escherichia coli;                                                  B = Trichosporon capitatum;                                                   C = Trichoderma viride;                                                       D = Candida lipolytica.                                                  

                                      TABLE II                                    __________________________________________________________________________    Elemental Analyses and Properties of Phosphonated Fatty Amides                                    Density                                                                            N.sup.30                                                                           % C      % H     % N     % P                                        30 C D    Exp. Theory                                                                            Exp.                                                                              Theory                                                                            Exp.                                                                              Theory                                                                            Exp.                                                                              Theory             __________________________________________________________________________    N,N-Dibutyl-9(10)-dibutylphosphono-                                            octadecanamide     0.9223                                                                             1.4534                                                                             68.94                                                                              69.46                                                                             12.06                                                                             12.35                                                                             2.46                                                                              2.38                                                                              5.01                                                                              5.27               N,N-Bis(2-ethoxyethyl)-9(10)-                                                  dibutylphosphonooctadecanamide                                                                   0.9501                                                                             1.4538                                                                             66.28                                                                              65.78                                                                             11.23                                                                             11.37                                                                             2.27                                                                              2.26                                                                              4.75                                                                              4.99               N-[9(10)-Dibutylphosphonoocta-                                                 decanoyl]-2,6-dimethylmorpholine                                                                 0.9661                                                                             1.4618                                                                             66.90                                                                              66.98                                                                             11.43                                                                             11.59                                                                             2.34                                                                              2.44                                                                              5.34                                                                              5.40               N-Ethyl-N-(3-ethoxypropyl)-9(10)-                                              dibutylphosphonooctadecanamide                                                                   0.9411                                                                             1.4541                                                                             67.27                                                                              67.20                                                                             11.18                                                                             11.02                                                                             2.38                                                                              2.38                                                                              5.18                                                                              5.26               N-[ 9(10)-Dibutylphosphonoocta-                                                decanoyl]piperidine                                                                              0.9385                                                                             1.4667                                                                             68.05                                                                              68.47                                                                             11.54                                                                             11.86                                                                             2.65                                                                              2.58                                                                              5.70                                                                              5.70               N-[9(10)-Dibutylphosphonoocta-                                                 decanoyl]-N'-methylpiperazine                                                                    0.9514                                                                             1.4605                                                                             67.02                                                                              66.83                                                                             11.32                                                                             11.36                                                                             4.85                                                                              5.01                                                                              5.32                                                                              5.55               N,N-Dimethyl-9(10)-dibutylphos-                                                phonooctadecanamide                                                                              0.9495                                                                             1.4559                                                                             66.53                                                                              66.76                                                                             11.44                                                                             12.01                                                                             2.68                                                                              2.78                                                                              6.28                                                                              6.15               N-[9(10)-Dibutylphosphonoocta-                                                 decanoyl]-4-methylpiperidine                                                                     0.9482                                                                             1.4643                                                                             69.30                                                                              68.90                                                                             11.52                                                                             11.93                                                                             2.41                                                                              2.51                                                                              5.31                                                                              5.56               N-Methyl-N-butyl-9(10)-dibutyl-                                                phosphonooctadecanamide                                                                          0.9150                                                                             1.4557                                                                             68.06                                                                              68.21                                                                             12.11                                                                             11.82                                                                             2.74                                                                              2.57                                                                              5.35                                                                              5.68               N-[9(10)-Dibutylphosphonoocta-                                                 decanoyl]morpholine                                                                              0.9740                                                                             1.4611                                                                             65.96                                                                              66.00                                                                             11.10                                                                             11.08                                                                             2.59                                                                              2.57                                                                              5.60                                                                              5.68               N-[11-Dibutylphosphonoundecanoyl]                                              morpholine         1.0233                                                                             1.4728                                                                             61.17                                                                              61.71                                                                             10.73                                                                             10.36                                                                             3.23                                                                              3.13                                                                              6.71                                                                              6.90               N-(12-Acetyl-12-carboethoxy-                                                   dodecanoyl)morpholine                                                                            --   --   65.68                                                                              65.78                                                                              9.92                                                                              9.87                                                                             3.56                                                                              3.68                                                                              --  --                 __________________________________________________________________________

We claim:
 1. A process for preparing a compound represented by theformula ##EQU1## wherein R is an alkyl radical containing from one tofour carbon atoms, and R' contains an amide nitrogen which may bederived from a dialkylamine, alkyl-alkoxyalkylamine or nitrogenheteroalicyclic, which process comprises reacting N,N-disubstitutedoleamide with a dialkyl phosphite using gamma radiation from cobalt-60to initiate free radical reaction.